tbuckley/cabot-search huggingface dataset:
Thymic epithelial cells require lipid kinase Vps34 for CD4 but not CD8 T cell selection
Authors: J. Luke Postoak, Wenqiang Song, Guan Yang, Xingyi Guo, Shiyun Xiao, Cherie E. Saffold, Jianhua Zhang, Sebastian Joyce, Nancy R. Manley, Lan Wu, Luc Van Kaer
Journal: The Journal of Experimental Medicine (2022)

The generation of a functional, self-tolerant T cell receptor (TCR) repertoire depends on interactions between developing thymocytes and antigen-presenting thymic epithelial cells (TECs). Cortical TECs (cTECs) rely on unique antigen-processing machinery to generate self-peptides specialized for T cell positive selection. In our current study, we focus on the lipid kinase Vps34, which has been implicated in autophagy and endocytic vesicle trafficking. We show that loss of Vps34 in TECs causes profound defects in the positive selection of the CD4 T cell lineage but not the CD8 T cell lineage. Utilizing TCR sequencing, we show that T cell selection in conditional mutants causes altered repertoire properties including reduced clonal sharing. cTECs from mutant mice display an increased abundance of invariant chain intermediates bound to surface MHC class II molecules, indicating altered antigen processing. Collectively, these studies identify lipid kinase Vps34 as an important contributor to the repertoire of selecting ligands processed and presented by TECs to developing CD4 T cells.
A Protumorigenic mDia2–MIRO1 Axis Controls Mitochondrial Positioning and Function in Cancer-Associated Fibroblasts
Authors: Michael Cangkrama, Huan Liu, James Whipman, Maria Zubair, Mai Matsushita, Michela Di Filippo, Manfred Kopf, Metello Innocenti, Sabine Werner
Journal: Cancer Research (2022)

Abstract Cancer-associated fibroblasts (CAF) are key regulators of tumorigenesis. Further insights into the tumor-promoting mechanisms of action of CAFs could help improve cancer diagnosis and treatment. Here we show that the formin mDia2 regulates the positioning and function of mitochondria in dermal fibroblasts, thereby promoting a protumorigenic CAF phenotype. Mechanistically, mDia2 stabilized the mitochondrial trafficking protein MIRO1. Loss of mDia2 or MIRO1 in fibroblasts or CAFs reduced the presence of mitochondria and ATP levels near the plasma membrane and at CAF-tumor cell contact sites, caused metabolic alterations characteristic of mitochondrial dysfunction, and suppressed the secretion of protumorigenic proteins. In mouse models of squamous carcinogenesis, genetic or pharmacologic inhibition of mDia2, MIRO1, or their common upstream regulator activin A inhibited tumor formation. Consistently, co-upregulation of mDia2 and MIRO1 in the stroma of various human cancers negatively correlated with survival. This work unveils a key role of mitochondria in the protumorigenic CAF phenotype and identifies an activin A–mDia2–MIRO1 signaling axis in CAFs with diagnostic and therapeutic potential. Significance: Inhibition of mDia2/MIRO1-mediated mitochondrial positioning in CAFs induces mitochondrial dysfunction and suppresses tumor growth, revealing a promising therapeutic strategy to target tumor–stroma cross-talk.
Temperature-sensitive polymers to promote heat-triggered drug release from liposomes: Towards bypassing EPR
Authors: Mohamadreza Amin, Twan Lammers, Timo L.M. ten Hagen
Journal: Advanced Drug Delivery Reviews (2022)

Heat-triggered drug release from temperature-sensitive nanocarriers upon the application of mild hyperthermia is a promising approach to achieve site-specific delivery of drugs. The combination of mild hyperthermia (41–42 °C) and temperature-sensitive liposomes (TSL) that undergo lipid phase-transition and drug release has been studied extensively and has shown promising therapeutic outcome in a variety of animal tumor models as well as initial indications of success in humans. Sensitization of liposomes to mild hyperthermia by means of exploiting the thermal behavior of temperature-sensitive polymers (TSP) provides novel opportunities. Recently, TSP-modified liposomes (TSPL) have shown potential for enhancing tumor-directed drug delivery, either by triggered drug release or by triggered cell interactions in response to heat. In this review, we describe different classes of TSPL, and analyze and discuss the mechanisms and kinetics of content release from TSPL in response to local heating. In addition, the impact of lipid composition, polymer and copolymer characteristics, serum components and PEGylation on the mechanism of content release and TSPL performance is addressed. This is done from the perspective of rationally designing TSPL, with the overall goal of conceiving efficient strategies to increase the efficacy of TSPL plus hyperthermia to improve the outcome of targeted anticancer therapy.
Dapagliflozin and Prevention of Kidney Disease Among Patients With Type 2 Diabetes: Post Hoc Analyses From the DECLARE-TIMI 58 Trial
Authors: Ofri Mosenzon, Itamar Raz, Stephen D. Wiviott, Meir Schechter, Erica L. Goodrich, Ilan Yanuv, Aliza Rozenberg, Sabina A. Murphy, Thomas A. Zelniker, Anna Maria Langkilde, Ingrid A.M. Gause-Nilsson, Martin Fredriksson, Peter A. Johansson, John P.H. Wilding, Darren K. McGuire, Deepak L. Bhatt, Lawrence A. Leiter, Avivit Cahn, Jamie P. Dwyer, Hiddo J.L. Heerspink, Marc S. Sabatine
Journal: Diabetes Care (2022)

In patients with moderate to severe albuminuric kidney disease, sodium-glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk.
Cardiac Autonomic Nerve Dysfunction Predicts Incident Retinopathy and Early Kidney Dysfunction in Adolescents With Type 1 Diabetes
Authors: Vallimayil Velayutham, Paul Benitez-Aguirre, Maria Craig, Yoon Hi Cho, Gerald Liew, Kim Donaghue
Journal: Diabetes Care (2022)

Cardiac autonomic neuropathy (CAN) may contribute to vascular complications in diabetes. We hypothesized that adolescents with CAN are at greater risk of diabetic retinopathy and early kidney dysfunction.In this prospective longitudinal study of 725 adolescents with type 1 diabetes without retinopathy and albuminuria at baseline, early CAN was defined as one or more abnormalities in seven heart rate tests derived from a 10-min electrocardiogram. Retinopathy was defined as the presence of one or more microaneurysms, early kidney dysfunction as an albumin excretion rate (AER) >7.5 μg/min, and albuminuria as an AER >20 μg/min. Multivariable generalized estimating equations were used to examine the association between CAN and retinopathy or early kidney dysfunction. Cox proportional hazards regression analysis was used to assess cumulative risks of incident retinopathy and albuminuria.At baseline, the mean age of the sample was 13.6 ± 2.6 years, 52% were male, and mean diabetes duration was 6.1 ± 3.3 years. Over a median follow-up of 3.8 (interquartile range 2.2-7.5) years, the complication rate 27% for retinopathy, 16% for early kidney dysfunction, and 3% for albuminuria. The mean study HbA1c was 72.3 ± 16 mmol/mmol (8.6 ± 1.4%). CAN predicted incident retinopathy (odds ratio 2.0 [95% CI 1.4, 2.9]) and early kidney dysfunction (1.4 [1.0, 2.0]) after adjusting for HbA1c and diabetes duration. CAN also predicted retinopathy (hazard ratio 1.57 [95% CI 1.09, 2.26]) and albuminuria (2.30 [1.05, 5.04]) independently of HbA1c.CAN predicted incident retinopathy and kidney dysfunction in adolescents with type 1 diabetes, likely reflecting autonomic microvascular dysregulation contributing to complications. Therefore, screening and interventions to reduce CAN may influence the risk of complications.
Science-Driven Nutritional Interventions for the Prevention and Treatment of Cancer
Authors: Léa Montégut, Rafael de Cabo, Laurence Zitvogel, Guido Kroemer
Journal: Cancer Discovery (2022)

Abstract In population studies, dietary patterns clearly influence the development, progression, and therapeutic response of cancers. Nonetheless, interventional dietary trials have had relatively little impact on the prevention and treatment of malignant disease. Standardization of nutritional interventions combined with high-level mode-of-action studies holds the promise of identifying specific entities and pathways endowed with antineoplastic properties. Here, we critically review the effects of caloric restriction and more specific interventions on macro- and micronutrients in preclinical models as well as in clinical studies. We place special emphasis on the prospect of using defined nutrition-relevant molecules to enhance the efficacy of established anticancer treatments. Significance: The avoidance of intrinsically hypercaloric and toxic diets contributes to the prevention and cure of cancer. In addition, specific diet-induced molecules such as ketone bodies and micronutrients, including specific vitamins, have drug-like effects that are clearly demonstrable in preclinical models, mostly in the context of immunotherapies. Multiple trials are underway to determine the clinical utility of such molecules.
The Need for a Medical Ideology
Authors: Allen Ruby
Journal: JAMA (1970)

There is considerable irony in the paradox which confronts the profession today. After years of earnest, often bitter, debate, the medical community has finally perceived that rapidly rising demands for its services, as well as an explosive new technology, together make inevitable a fundamental transformation in the quality, scope, and nature of health-care delivery. It is precisely this perception, this awareness, which has led to a miscalculation of immense— possibly fatal—dimensions. For if the clamor for more and better medical care is the goal of technical advance, so is technology seen as the only agent of deliverance from the crisis imposed by rising expectations. What has emerged is a simple strategy: medical technology must be generated and deployed as quickly as possible. If only a sufficiently sophisticated technology can be developed, the prevailing ethic says, the medical needs of this profession's constituency can be satisfied. We submit that this ethic
ESBL plasmids in Klebsiella pneumoniae: diversity, transmission and contribution to infection burden in the hospital setting
Authors: Jane Hawkey, Kelly L. Wyres, Louise M. Judd, Taylor Harshegyi, Luke Blakeway, Ryan R. Wick, Adam W. J. Jenney, Kathryn E. Holt
Journal: Genome Medicine (2022)

Abstract Background Resistance to third-generation cephalosporins, often mediated by extended-spectrum beta-lactamases (ESBLs), is a considerable issue in hospital-associated infections as few drugs remain for treatment. ESBL genes are often located on large plasmids that transfer horizontally between strains and species of Enterobacteriaceae and frequently confer resistance to additional drug classes. Whilst plasmid transmission is recognised to occur in the hospital setting, the frequency and impact of plasmid transmission on infection burden, compared to ESBL + strain transmission, is not well understood. Methods We sequenced the genomes of clinical and carriage isolates of Klebsiella pneumoniae species complex from a year-long hospital surveillance study to investigate ESBL burden and plasmid transmission in an Australian hospital. Long-term persistence of a key transmitted ESBL + plasmid was investigated via sequencing of ceftriaxone-resistant isolates during 4 years of follow-up, beginning 3 years after the initial study. Results We found 25 distinct ESBL plasmids. We identified one plasmid, which we called Plasmid A, that carried bla CTX-M-15 in an IncF backbone similar to pKPN-307. Plasmid A was transmitted at least four times into different Klebsiella species/lineages and was responsible for half of all ESBL episodes during the initial 1-year study period. Three of the Plasmid A-positive strains persisted locally 3–6 years later, and Plasmid A was detected in two additional strain backgrounds. Overall Plasmid A accounted for 21% of ESBL + infections in the follow-up period. Conclusions Here, we systematically surveyed ESBL strain and plasmid transmission over 1 year in a single hospital network. Whilst ESBL plasmid transmission events were rare in this setting, they had a significant and sustained impact on the burden of ceftriaxone-resistant and multidrug-resistant infections. If onward transmission of Plasmid A-carrying strains could have been prevented, this may have reduced the number of opportunities for Plasmid A to transmit and create novel ESBL + strains, as well as reducing overall ESBL infection burden.
Cardiovascular Autonomic Neuropathy Is Associated With Increased Glucose Variability in People With Type 1 Diabetes
Authors: Sara H. Naaman, Hatice I. Mizrak, Nanna Lind, Jens C. Laursen, Huda Kufaishi, Marie M.B. Christensen, Ajenthen G. Ranjan, Kirsten Nørgaard, Christian S. Hansen
Journal: Diabetes Care (2022)

OBJECTIVE We investigated the association between the cardiovascular autonomic neuropathy (CAN) diagnosis and glucose variability (GV) in type 1 diabetes (T1D), as autonomic dysfunction previously has been associated with increased GV. RESEARCH DESIGN AND METHODS CAN was assessed by three recommended cardiovascular reflex tests (CARTs). Glucose metrics were obtained from 10-day blinded continuous glucose monitoring (CGM). Between-group differences in GV indices were assessed by regression analyses in 24 participants with T1D with CAN and 24 matched control subjects without CAN. RESULTS The CAN diagnosis was associated with 4.9% (95% CI 1.0, 8.7) higher coefficient of variation (CV) (P = 0.014), 0.7 mmol/L (0.3, 1.1) higher SD (P = 0.002) of glucose, and 1.4 mmol/mol (0.0, 2.7) higher mean amplitude of glycemic excursions (P = 0.047). Lower measures of CARTs were associated with higher CV, SD, and time above range values. CONCLUSIONS The CAN diagnosis associates with a significantly higher GV in T1D, despite a high prevalence of routine CGM use.
First STEPS: Primary Outcomes of a Randomized, Stepped-Care Behavioral Clinical Trial for Parents of Young Children With New-Onset Type 1 Diabetes
Authors: Marisa E. Hilliard, Carrie Tully, Maureen Monaghan, Tom Hildebrandt, Christine H. Wang, John R. Barber, Lauren Clary, Katherine Gallagher, Wendy Levy, Fran Cogen, Celia Henderson, Lefkothea Karaviti, Randi Streisand
Journal: Diabetes Care (2022)

Despite the emotional challenges of parental adjustment to a child's type 1 diabetes diagnosis and the unique complexities of early childhood, there are few programs designed to meet the needs of parents of young children at new onset. This study evaluated First STEPS (Study of Type 1 in Early childhood and Parenting Support), a stepped-care behavioral intervention designed to support parents' psychosocial functioning and promote children's glycemic outcomes.Using a two-site randomized clinical trial design, parents (n = 157) of children aged 1-6 years completed baseline data within 2 months of diabetes diagnosis and were randomly assigned to intervention (n = 115) or usual care (n = 42) for 9 months. Intervention steps included: 1) peer parent coaching, with step-ups to 2) structured behavioral counseling and 3) professional consultations with a diabetes educator and psychologist, based on parent mood and child HbA1c. Participants completed follow-ups at 9 and 15 months postrandomization. Primary outcomes were parent depressive symptoms and child HbA1c.Depressive symptoms improved in both groups, and intervention parents had significantly lower depressive symptoms at the 9- and 15-month follow-ups compared with usual care. HbA1c decreased in both groups, but there were no between-group differences at 9 or 15 months.First STEPS improved parents' mood following young children's type 1 diabetes diagnosis. Results indicate likely benefits of parent coach support, supplemented by intervention intensifications, including behavioral intervention and diabetes education. This model has high potential for patient engagement. The absence of a medical intervention component may explain null findings for HbA1c; incorporating targeted behavioral support for intensive diabetes treatment may maximize intervention impact.
Current Medical Literature
Journal: JAMA (1935)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Minimal Contact Treatment for Smoking Cessation
Authors: Stephen P. Fortmann
Journal: JAMA (1988)

To determine the effectiveness of nicotine polacrilex combined with self-administered relapse prevention materials in maintaining smoking cessation, we conducted a randomized, double-blind, placebo controlled trial. Volunteers aged 18 to 65 years responding to media announcements were required to quit smoking for 48 hours without assistance. Of 1844 potential participants, 136 were medically excluded, 535 declined to make a quit attempt, and 573 were unable to quit, leaving 600 participants (35%) who were randomized. Eight self-help relapse prevention modules were mailed weekly. Gum was used either ad lib for smoking urges or on a fixed, hourly schedule (12 pieces per day). Only 15% of the subjects in each gum group stopped using the gum altogether because of side effects, but only 20% of the ad lib groups and 40% of the fixed-dosage group used at least eight pieces of gum per day during the first week. The abstinence rates (for at least seven days) at the six-month follow-up were 31% in both active gum groups and 22% in the placebo and no gum groups. Relapse rates in the two active gum groups were about half those in the placebo and no gum groups. Nicotine polacrilex may be a useful adjunct to minimal contact smoking cessation formats, which have broad appeal. Also, minimal contact relapse prevention programs may assist physicians in helping patients to maintain smoking cessation using nicotine polacrilex. (<i>JAMA</i>1988;260:1575-1580)
Clinical Images: Chronic, refractory childhood‐onset cutaneous lupus erythematosus of the face responsive to lenalidomide
Authors: Matthew A. Sherman, Hemalatha Srinivasalu, A. Yasmine Kirkorian, Michael A. Cardis
Journal: Arthritis & Rheumatology (2022)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
New Mental Health Crisis Hotline
Authors: Melissa Suran
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Comparing Spending in Medicare Advantage and Accountable Care Organizations—Is Plan–Health Care System Integration the Future?
Authors: David J. Meyers
Journal: JAMA Network Open (2022)

Ravi B. Parikh, MD, MPP; Ezekiel J. Emanuel, MD, PhD; Colleen M. Brensinger, MS; Connor W. Boyle, BA; Eboni G. Price-Haywood, MD, MPH; Jeffrey H. Burton, PhD; Sabrina B. Heltz, ASA; Amol S. Navathe, MD, PhD
Data Errors in Table 3
Journal: JAMA Network Open (2022)

Maninder K. Kahlon, PhD; Nazan S. Aksan, PhD; Rhonda Aubrey, MHI; Jenn Barnes, MA; Nicole Clark, MBA; Maria Cowley-Morillo, BS; Lindsey Engelman, MA, MSCRP; Julia Guerra, MSc; Alejandro Guevara; Allison Marshall, PhD; Deanna M. Hoelscher, PhD
Statin Usage in Primary Prevention—Comparing the USPSTF Recommendations With the AHA/ACC/Multisociety Guidelines
Authors: Neil J. Stone, Philip Greenland, Scott M. Grundy
Journal: JAMA Cardiology (2022)

This Editorial compares the US Preventive Services Task Force (USPSTF) recommendations with the American Heart Association/American College of Cardiology (AHA/ACC)/multisociety guidelines on statin usage in primary prevention.
Identification of key microRNAs as predictive biomarkers of Nilotinib response in chronic myeloid leukemia: a sub-analysis of the ENESTxtnd clinical trial
Authors: Ryan Yen, Sarah Grasedieck, Andrew Wu, Hanyang Lin, Jiechuang Su, Katharina Rothe, Helen Nakamoto, Donna L. Forrest, Connie J. Eaves, Xiaoyan Jiang
Journal: Leukemia (2022)
Evaluating how clear the questions being investigated in randomised trials are: systematic review of estimands
Authors: Suzie Cro, Brennan C Kahan, Sunita Rehal, Anca Chis Ster, James R Carpenter, Ian R White, Victoria R Cornelius
Journal: BMJ (2022)

To evaluate how often the precise research question being addressed about an intervention (the estimand) is stated or can be determined from reported methods, and to identify what types of questions are being investigated in phase 2-4 randomised trials.
Thromboprophylaxis After Hip or Knee Arthroplasty
Authors: Noel C. Chan, Mohit Bhandari
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal